Transcranial direct current stimulation for provoked vestibulodynia: What roles do psychosexual factors play in treatment response?

There is growing evidence that provoked vestibulodynia (PVD), a frequent and debilitating condition, is characterized by central sensitization. This study aimed to examine predictive factors of transcranial direct current stimulation (tDCS) efficacy in this chronic pain population. Exploratory analysis derived from a randomized controlled trial was performed to assess predictors of pain reduction among 39 women with PVD who received 10 daily sessions of either active or sham tDCS. Clinical characteristics (e.g. pain intensity, duration and pain sensitivity) and psychosexual factors (e.g. pain catastrophizing, pain-related fear, anxiety, depressive symptoms and vaginal penetration cognitions) were assessed at baseline and used to predict tDCS response at 3-month follow-up. Analysis revealed that higher depressive symptoms and lower negative self-image cognitions were significant predictors of pain reduction at follow-up and accounted for 62.3% of the variance in the active tDCS group. Higher genital incompatibility cognitions were related to poorer response, regardless of treatment group. These findings suggest that women with PVD presenting higher depressive symptoms and lower levels of negative self-image cognitions could derive greater benefits from tDCS. These results suggest that tDCS could be effective in a subgroup of women with PVD - a possibility worth exploring with future prospective larger studies.

Patient-partner engagement at the Centre de recherche du CHUS in the Province of Québec, Canada: from an intuitive methodology to outreach after three years of implementation.

BACKGROUND: Medical societies and funding agencies strongly recommend that patients be included as partners in research publications and grant applications. Although this "top-down" approach is certainly efficient at forcing this new and desirable type of collaboration, our past experience demonstrated that it often results in an ambiguous relationship as not yet well integrated into the cultures of either patients' or the researchers'. The question our group raised from this observation was: "How to generate a cultural shift toward a fruitful and long-lasting collaboration between patients and researchers? A "bottom-up" approach was key to our stakeholders. The overall objective was to build a trusting and bidirectional-ecosystem between patients and researchers. The specific objectives were to document: 1) the steps that led to the development of the first patient-partner strategic committee within a research center in the Province of Québec; 2) the committee's achievements after 3 years. METHODS: Eighteen volunteer members, 12 patient-partners and 6 clinician/institutional representatives, were invited to represent the six research themes of the Centre de recherche du CHU de Sherbrooke (CRCHUS) (Quebec, Canada). Information on the services offered by Committee was disseminated internally and to external partners. Committee members satisfaction was evaluated. RESULTS: From May 2017 to April 2020, members attended 29 scheduled and 6 ad hoc meetings and contributed to activities requiring over 1000 h of volunteer time in 2018-2019 and 1907 h in the 2019-2020 period. The Committee's implication spanned governance, expertise, and knowledge transfer in research. Participation in these activities increased annually at local, provincial, national and international levels. The Patient-Partner Committee collaborated with various local (n = 7), provincial (n = 6) and national (n = 4) partners. Member satisfaction with the Committee's mandate and format was 100%. CONCLUSIONS: The CRCHUS co-constructed a Patient-Partner Strategic Committee which resulted in meaningful bilateral, trusting and fruitful collaborations between patients, researchers and partners. The "bottom-up" approach - envisioned and implemented by the Committee, where the expertise and the needs of patients complemented those of researchers, foundations, networks and decision-makers - is key to the success of a cultural shift. The CRCHUS Committee created a hub to develop the relevant intrinsic potential aimed at changing the socio-cultural environment of science.

[The right of users to serve patients and caregivers]. / Le droit des usagers au service des patients et des aidants.

What is the common thread to ensure that the caregiver-patient relationship plays an integral role in healthcare facilities? The origins date to 1973, with the evolution of the nursing programme. The patient moves from the object stage to the subject stage. To date, he is considered a full "person" in all aspects, psychic, physical, cultural and social.

Impact of heterogeneous properties of soil and LNAPL on surfactant-enhanced capillary desaturation.

This paper investigates low-concentration (<1wt%) surfactant flushing when used as a follow-up technology for multiphase vacuum extraction on heterogeneous sites. Challenges posed by soil permeability, pore-size distribution, mineralogy, light non-aqueous phase liquid (LNAPL) weathering and groundwater hardness were quantified through batch and soil column tests. Compatibility issues between the mixed mineralogy soils, hard groundwater, mixed LNAPL and usual anionic surfactants were observed. The selected solution was a Winsor type I system promoting an interfacial tension of 0.06mN/m between the site LNAPL and the amphoteric surfactant CAS in aqueous solution at pH12. Surfactant loses to adsorption and pore media plugging were observed in the fine soil fraction. The capillary desaturation curves (CDC) obtained with the column tests suggested mixed-wettability behavior. The soil permeability strongly influenced LNAPL recovery, as expressed by the relationship obtained between capillary numbers (NCa) and hydraulic gradients. In this case, the critical NCa, marking the onset of capillary desaturation, could only be obtained with realistic hydraulic gradients in the coarse soil fraction. At those gradients, potential LNAPL recovery was 30% at the most. Unlike previously published CDCs, the relationship between NCa (log-scale) and LNAPL recovery was not linear but dependant on residual LNAPL saturation.

Statistical analysis of fractionation resistance by functional category and expression.

BACKGROUND: The current literature establishes the importance of gene functional category and expression in promoting or suppressing duplicate gene loss after whole genome doubling in plants, a process known as fractionation. Inspired by studies that have reported gene expression to be the dominating factor in preventing duplicate gene loss, we analyzed the relative effect of functional category and expression. METHODS: We use multivariate methods to study data sets on gene retention, function and expression in rosids and asterids to estimate effects and assess their interaction. RESULTS: Our results suggest that the effect on duplicate gene retention fractionation by functional category and expression are independent and have no statistical interaction. CONCLUSION: In plants, functional category is the more dominant factor in explaining duplicate gene loss.

Efficacy of transcranial direct-current stimulation in women with provoked vestibulodynia.

BACKGROUND: Provoked vestibulodynia is a highly prevalent condition characterized by acute recurrent pain located at the vaginal entrance in response to pressure application or attempted vaginal penetration. Despite a wide variety of treatments offered to women with provoked vestibulodynia, a high proportion of women are refractory to conventional treatment. Transcranial direct-current stimulation is a noninvasive brain stimulation technique that has been shown effective for improving various chronic pain conditions. Growing evidence suggests that the central nervous system could play a key role in provoked vestibulodynia. Targeting the central nervous system could therefore be a promising treatment for women with provoked vestibulodynia. OBJECTIVE: The purpose of this study was to evaluate and compare the efficacy of active and sham transcranial direct-current stimulation in reducing pain intensity during intercourse in patients with provoked vestibulodynia. STUDY DESIGN: We conducted a triple-blind, parallel-group, randomized controlled trial. Women aged 17-45 years diagnosed with provoked vestibulodynia by a gynecologist using a validated protocol were randomized to 10 sessions of either active transcranial direct-current stimulation (intensity = 2 mA) or 10 sessions of sham transcranial direct-current stimulation, over a 2-week period. Both active and sham transcranial direct-current stimulation were applied for 20 minutes, with the anode positioned over the primary motor cortex, and the cathode over the contralateral supraorbital area. Outcome measures were collected at baseline, 2 weeks after treatment, and at 3-month follow-up by an evaluator blinded to group assignment. The primary objective was to assess pain intensity during intercourse, using a numerical rating scale. Secondary outcomes focused on sexual function and distress, vestibular sensitivity, psychological distress, treatment satisfaction, and patient impression of change. Statistical analyses were conducted on the intention-to-treat basis, and treatment effects were evaluated using a mixed linear model for repeated measures. RESULTS: A total of 40 patients were randomly assigned to receive either active (n = 20) or sham (n = 20) transcranial direct-current stimulation treatments from November 2014 through February 2016. Baseline characteristics were similar between the active and sham transcranial direct-current stimulation groups. In full compliance with the study protocol, every participant followed all courses of the study treatment, including assessments at 2-week and 3-month follow-up. Pain during sexual intercourse was not significantly different between active and sham treatment groups 2 weeks after treatment (P = .84) and at follow-up (P = .09). Mean baseline and 2-week assessment pain intensity were, respectively, 6.8 (95% confidence interval, 5.9-7.7) and 5.6 (95% confidence interval, 4.7-6.5) for active transcranial direct-current stimulation (P = .03) vs 7.5 (95% confidence interval, 6.6-8.4) and 5.7 (95% confidence interval, 4.8-6.6) for sham transcranial direct-current stimulation (P = .001). Nonsignificant differences between the 2 groups were also found in their sexual function and distress after treatment (P > .20) and at follow-up (P > .10). Overall, at 2-week assessment 68% assigned to active transcranial direct-current stimulation reported being very much, much, or slightly improved compared to 65% assigned to sham transcranial direct-current stimulation (P = .82), and still comparable at follow-up: 42% vs 65%, respectively (P = .15). CONCLUSION: Findings suggest that active transcranial direct-current stimulation is not more effective than sham transcranial direct-current stimulation for reducing pain in women with provoked vestibulodynia. Likewise, no significant effects were found on sexual function, vestibular sensitivity, or psychological distress.

Efficacy of transcranial direct-current stimulation (tDCS) in women with provoked vestibulodynia: study protocol for a randomized controlled trial.

BACKGROUND: Provoked vestibulodynia is the most common form of vulvodynia. Despite its high prevalence and deleterious sexual, conjugal, and psychological repercussions, effective evidence-based interventions for provoked vestibulodynia remain limited. For a high proportion of women, significant pain persists despite the currently available treatments. Growing evidence suggests that the central nervous system (CNS) could play a key role in provoked vestibulodynia; thus, treatment targeting the CNS, rather than localized dysfunctions, may be beneficial for women suffering from provoked vestibulodynia. In this study, we aim to build on the promising results of a previous case report and evaluate whether transcranial direct-current stimulation, a non-invasive brain stimulation technique targeting the CNS, could be an effective treatment option for women with provoked vestibulodynia. METHODS/DESIGN: This single-center, triple-blind, parallel group, randomized, controlled trial aims to compare the efficacy of transcranial direct-current stimulation with sham transcranial direct-current stimulation in women with provoked vestibulodynia. Forty women diagnosed with provoked vestibulodynia by a gynecologist, following a standardized treatment protocol, are randomized to either active transcranial direct-current stimulation treatment for ten sessions of 20 minutes at an intensity of 2 mA or sham transcranial direct-current stimulation over a 2-week period. Outcome measures are collected at baseline, 2 weeks after treatment and at 3-month follow-up. The primary outcome is pain during intercourse, assessed with a numerical rating scale. Secondary measurements focus on the sexual function, vestibular pain sensitivity, psychological distress, treatment satisfaction, and the patient's global impression of change. DISCUSSION: To our knowledge, this study is the first randomized controlled trial to examine the efficacy of transcranial direct-current stimulation in women with provoked vestibulodynia. Findings from this trial are expected to provide significant information about a promising intervention targeting the centralization of pain in women with provoked vestibulodynia. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02543593 . Registered on September 4, 2015.

Romiplostim efficacy in an acute myeloid leukemia patient with transfusion refractory thrombocytopenia.

BACKGROUND: Refractoriness to platelet (PLT) transfusion is a feared, life-threatening complication in hematology-oncology patients. Despite increased PLT requirement and treatment costs, the clinical management is difficult and these patients had less favorable outcomes. CASE REPORT: We report on the efficacy of the thrombopoietic agent romiplostim in a patient with acute myeloid leukemia with chemotherapy-induced transfusion-refractory thrombocytopenia. CONCLUSION: Romiplostim could be very helpfull in the management of AML patients with transfusion refractory thrombocytopenia.

Foveal damage in habitual poppers users.

OBJECTIVE: To describe foveal damage in habitual use of poppers, a popular recreational drug. METHODS: Retrospective observational case series. Six patients with bilateral vision loss after chronic popper inhalation were seen in 4 university-based ophthalmology departments. Symptoms, medical history, ophthalmic examination, and functional and morphological tests are described. RESULTS: All patients experienced progressive bilateral vision loss, with central photopsia in 2 cases. Initial visual acuities ranged from 20/50 to 20/25. In all patients, a bilateral yellow foveal spot was present that, by optical coherence tomography, was associated with disruption of the outer segments of foveal cones. Functional and anatomical damage was restricted to the fovea. The poppers involved were identified as isopropyl nitrite in 3 cases. Four patients showed anatomical and/or functional improvement over several months after discontinuing popper inhalation. CONCLUSIONS: Repeated inhalation of poppers may be associated with prolonged bilateral vision loss due to the disruption of foveal cone outer segments. Retinal damage may progressively improve following drug discontinuation.

RhoGDI3 and RhoG: Vesicular trafficking and interactions with the Sec3 Exocyst subunit.

RhoGDIs are negative regulators of small GTP-binding proteins of the Rho family, which have essential cellular functions in most aspects of actin-based morphology and motility processes. They extract Rho proteins from membranes, keep them in inactive rhoGDI/Rho complexes and eventually deliver them again to specific membranes in response to cellular signals. RhoGDI3, the most divergent member of the rhoGDI family, is well suited to document the underlying molecular mechanisms, since the active and inactive forms of its cellular target, RhoG, have well-separated subcellular localizations. In this study, we investigate trafficking structures and molecular interactions involved in rhoGDI3-mediated shuttling of RhoG between the Golgi and the plasma membrane.Bimolecular fluorescence complementation and acceptor-photobleaching FRET experiments suggest that rhoGDI3 and RhoG form complexes on Golgi and vesicular structures in mammalian cells. 4D-videomicroscopy confirms this localization, and show that RhoG/rhoGDI3-labelled structures are less dynamic than RhoG and rhoGDI3-labeled vesicles, consistent with the inhibitory function of rhoGDI3. Next, we identify the Exocyst subunit Sec3 as a candidate rhoGDI3 partner in cells. RhoGDI3 relocates a subcomplex of the Exocyst (Sec3 and Sec8) from the cytoplasm to the Golgi, while Sec6 is unaffected. Remarkably, Sec3 increases the level of GTP-bound endogenous RhoG, the RhoG-dependent induction of membrane ruffles, and the formation of intercellular tunneling nanotube-like protrusions.Altogether, our study identifies a novel link between vesicular traffic and the regulation of Rho proteins by rhoGDIs. It also suggests that components of the Exocyst machinery may be involved in RhoG functions, possibly regulated by rhoGDI3.

Altered CD4+ T cell phenotype and function determine the susceptibility to mucosal candidiasis in transgenic mice expressing HIV-1.

The impairments of protective mucosal immunity which cause susceptibility to oropharyngeal candidiasis (OPC) in HIV infection remain undefined. This study used a model of OPC in CD4C/HIV MutA transgenic (Tg) mice expressing Rev, Env, and Nef of HIV-1 to investigate the role of transgene expressing dendritic cells (DCs) and CD4+ T cells in maintenance of chronic oral carriage of Candida albicans. DCs were depleted in the Tg mice and had an immature phenotype, with low expression of MHC class II and IL-12. CD4+ T cells were quantitatively reduced in the oral mucosa, cervical lymph nodes (CLNs) and peripheral blood of the Tg mice, and displayed a polarization toward a nonprotective Th2 response. Proliferation of CLN CD4+ T cells from infected Tg mice in response to C. albicans Ag in vitro was abrogated and the cells failed to acquire an effector phenotype. Coculture of C. albicans-pulsed DCs with CD4+ T cells in vitro showed that Tg expression in either or both of these cell populations sharply reduced the proliferation of CD4+ T cells and their production of IL-2. Finally, transfer of naive non-Tg CD4+ T cells into these Tg mice restored proliferation to C. albicans Ag and sharply reduced oral burdens of C. albicans. Overall, these results indicate that defective CD4+ T cells primarily determine the susceptibility to chronic carriage of C. albicans in these Tg mice.

Uncoupling of inhibitory and shuttling functions of rho GDP dissociation inhibitors.

Rho GDP dissociation inhibitors (rhoGDIs) are postulated to regulate the activity of small G proteins of the Rho family by a shuttling process involving the extraction of Rho from donor membranes, the formation of the inhibitory cytosolic Rho/rhoGDI complexes, and delivery of Rho to target membranes. However, the role of rhoGDIs in site-specific membrane targeting or extraction of Rho is still poorly understood. Here we investigated the molecular functions of two rhoGDIs, the specific rhoGDI-3 and the less specific but well studied rhoGDI-1, in HeLa cells using structure-based mutagenesis of the rhoGDI protein. We identified two sites in rhoGDI, which form conserved interactions with their Rho target, whose mutation results in the uncoupling of inhibitory and shuttling functions of rhoGDIs: D66GDI-3 (equivalent to D45GDI-1), a conserved residue in the helix-loop-helixGDI/switch 1Rho interface, and D206GDI-3 (equivalent to D185GDI-1) in the beta-sandwichGDI/switch 2Rho interface. Mutations of both sites result in the loss of rhoGDI-3 or rhoGDI-1 inhibitory activity but not of their ability to form cytosolic complexes with RhoG or Cdc42 in vivo. Remarkably, the mutants were detected at Rho-induced membrane ruffles or protrusions where they co-localized with RhoG or Cdc42, likely identifying for the first time the site of extraction of a Rho protein by a rhoGDI in vivo. We propose that these mutations act by modifying the steady-state kinetics of the shuttling process regulated by rhoGDIs, such that transient steps at the cell membranes now become detectable. They should provide valuable tools for future investigations of the dynamics of membrane extraction or delivery of Rho proteins and their regulation by cellular partners.

RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain.

Guanine nucleotide dissociation inhibitors (GDIs) regulate both GDP/GTP and membrane association/dissociation cycles of Rho/Rac and Rab proteins.RhoGDI-3 is distinguishable from other rhoGDI proteins by its partial association with a detergent-resistant subcellular fraction. Here, we investigate the activity of this unusual rhoGDI using confocal laser scanning microscopy, immuno-isolation, and rhoGDI-3 mutants. We establish that the noncytosolic fraction of rhoGDI-3 is associated with the Golgi apparatus. The domain involved in this association is the unique N-terminal segment of rhoGDI-3 predicted to form an amphipathic alpha helix. This peptide is indispensable for Golgi association of rhoGDI-3 and sufficient to address a green fluorescent protein to the Golgi apparatus. Site-directed mutations, decreasing the hydrophobic surface of the helix, localize rhoGDI-3 into the cytoplasm. We establish that rhoGDI-3 is able to inhibit activation of the RhoG protein and to target this protein to the Golgi apparatus. Furthermore, we demonstrate the importance of the rhoGDI-3 N-terminal segment for both Golgi targeting and stability of the cytoplasmic RhoG/rhoGDI-3 complex. RhoGDI-3 is the first example of a GDI directly involved in the delivery of a Rho protein to a specific subcellular compartment.